Alzheimer's Disease and Cognitive Decline in Patients with Cardiovascular Diseases Along the Heart-Brain Axis.

Background: We hypothesize that Alzheimer's disease (AD)-related pathology may accelerate cognitive decline in patients with cardiovascular diseases. Objective: To investigate the association between blood-based biomarkers of AD, astrocyte activation, and neurodegeneration and cognitive decline. Methods: From the multi-center Heart-Brain study, we included 412 patients with heart failure, carotid occlusive disease or vascular cognitive impairment (age:68.6±9.0) and 128 reference participants (65.7±7.5). Baseline amyloid-ß42/40 (Aß42/40), phosphorylated-tau181 (pTau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) were determined using SiMoA (Quanterix). Memory, attention, language, and executive functioning were evaluated (follow-up:2.1±0.3 years). We applied linear mixed models with terms for biomarker, time and biomarker*time interactions, adjusted for age, sex, education, and site, to assess associations between biomarkers and cognitive decline. Results: Among patients, Aß42/40 was not associated with cognitive performance at baseline. However, lower Aß42/40 was associated with steeper decline in global cognition (ß±SE:0.04±0.02). Higher pTau181 was associated with worse baseline performance on global cognition (-0.14±0.04) and memory (-0.31±0.09) and with steeper decline in global cognition (-0.07±0.02), memory (-0.09±0.04), attention (-0.05±0.02), and language (-0.10±0.03). Higher GFAP was associated with worse baseline performance on global cognition (-0.22±0.05), memory (-0.43±0.10), attention (-0.14±0.06), language (-0.15±0.05), and executive functioning (-0.15±0.05) and steeper decline in global cognition (-0.05±0.01). Higher NfL was associated with worse baseline performance on global cognition (-0.16±0.04), memory (-0.28±0.09), attention (-0.20±0.06), and executive functioning (-0.10±0.04), but was not associated with performance over time. In reference participants, no associations were found. Conclusions: Our findings suggest that blood-based biomarkers of AD-related pathology predict cognitive decline in patients with cardiovascular diseases.

Trimetazidine in heart failure with preserved ejection fraction: a randomized controlled cross-over trial.

AIMS: Impaired myocardial energy homeostasis plays an import role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). Left ventricular relaxation has a high energy demand, and left ventricular diastolic dysfunction has been related to impaired energy homeostasis. This study investigated whether trimetazidine, a fatty acid oxidation inhibitor, could improve myocardial energy homeostasis and consequently improve exercise haemodynamics in patients with HFpEF. METHODS AND RESULTS: The DoPING-HFpEF trial was a phase II single-centre, double-blind, placebo-controlled, randomized cross-over trial. Patients were randomized to trimetazidine treatment or placebo for 3 months and switched after a 2-week wash-out period. The primary endpoint was change in pulmonary capillary wedge pressure, measured with right heart catheterization at multiple stages of bicycling exercise. Secondary endpoint was change in myocardial phosphocreatine/adenosine triphosphate, an index of the myocardial energy status, measured with phosphorus-31 magnetic resonance spectroscopy. The study included 25 patients (10/15 males/females; mean (standard deviation) age, 66 (10) years; body mass index, 29.8 (4.5) kg/m2 ); with the diagnosis of HFpEF confirmed with (exercise) right heart catheterization either before or during the trial. There was no effect of trimetazidine on the primary outcome pulmonary capillary wedge pressure at multiple levels of exercise (mean change 0 [95% confidence interval, 95% CI -2, 2] mmHg over multiple levels of exercise, P = 0.60). Myocardial phosphocreatine/adenosine triphosphate in the trimetazidine arm was similar to placebo (1.08 [0.76, 1.76] vs. 1.30 [0.95, 1.86], P = 0.08). There was no change by trimetazidine compared with placebo in the exploratory parameters: 6-min walking distance (mean change of -6 [95% CI -18, 7] m vs. -5 [95% CI -22, 22] m, respectively, P = 0.93), N-terminal pro-B-type natriuretic peptide (5 (-156, 166) ng/L vs. -13 (-172, 147) ng/L, P = 0.70), overall quality-of-life (KCCQ and EQ-5D-5L, P = 0.78 and P = 0.51, respectively), parameters for diastolic function measured with echocardiography and cardiac magnetic resonance, or metabolic parameters. CONCLUSIONS: Trimetazidine did not improve myocardial energy homeostasis and did not improve exercise haemodynamics in patients with HFpEF.

AV junction ablation and cardiac resynchronization for patients with permanent atrial fibrillation and narrow QRS: the APAF-CRT mortality trial.

AIMS: In patients with atrial fibrillation (AF) and heart failure (HF), strict and regular rate control with atrioventricular junction ablation and biventricular pacemaker (Ablation + CRT) has been shown to be superior to pharmacological rate control in reducing HF hospitalizations. However, whether it also improves survival is unknown. METHODS AND RESULTS: In this international, open-label, blinded outcome trial, we randomly assigned patients with severely symptomatic permanent AF >6 months, narrow QRS (≤110 ms) and at least one HF hospitalization in the previous year to Ablation + CRT or to pharmacological rate control. We hypothesized that Ablation + CRT is superior in reducing the primary endpoint of all-cause mortality. A total of 133 patients were randomized. The mean age was 73 ± 10 years, and 62 (47%) were females. The trial was stopped for efficacy at interim analysis after a median of 29 months of follow-up per patient. The primary endpoint occurred in 7 patients (11%) in the Ablation + CRT arm and in 20 patients (29%) in the Drug arm [hazard ratio (HR) 0.26, 95% confidence interval (CI) 0.10-0.65; P = 0.004]. The estimated death rates at 2 years were 5% and 21%, respectively; at 4 years, 14% and 41%. The benefit of Ablation + CRT of all-cause mortality was similar in patients with ejection fraction (EF) ≤35% and in those with >35%. The secondary endpoint combining all-cause mortality or HF hospitalization was significantly lower in the Ablation + CRT arm [18 (29%) vs. 36 (51%); HR 0.40, 95% CI 0.22-0.73; P = 0.002]. CONCLUSIONS: Ablation + CRT was superior to pharmacological therapy in reducing mortality in patients with permanent AF and narrow QRS who were hospitalized for HF, irrespective of their baseline EF. STUDY REGISTRATION: ClinicalTrials.gov Identifier: NCT02137187.

Accuracy of oscillometric blood pressure measurement in atrial fibrillation.

OBJECTIVE: The primary aim of this study was to assess the accuracy of automated oscillometry (AO) in outpatients with atrial fibrillation (AF). The secondary aim was to explore whether AO accuracy is influenced by beat-to-beat blood pressure (BP) variability or heart frequency (HF). METHODS: Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured by AO and beat-to-beat BP using a validated Volume Clamp Method (VCM) technique. AO accuracy was analyzed separately in tertiles of beat-to-beat BP variability and HF. RESULTS: The main study included 58 AF and 38 sinus rhythm (SR) patients in whom the Welch Allyn Spot Vital Signs (WASVS) was used. An auxiliary study in 23 AF patients used the Philips M3002A IntelliVue ×2. For AF and SR patients, respectively, SBP by WASVS deviated by +0.1 (±14.8) mmHg and -7.9 (±15.7) mmHg from VCM. WASVS-DBP was higher than VCM in AF and SR by 6.3 (±9.2) mmHg and 5.0 (±7.7) mmHg, respectively. High beat-to-beat BP variability and high HF decreased WASVS accuracy for both SBP and DBP. SBP and DBP measurements by Philips M3002A IntelliVue ×2 deviated by -6.8 (±13.2) mmHg and 9.4 (±8.1) mmHg, respectively. CONCLUSION: Overall, AO accuracy in AF is limited; in individual patients, AO inaccuracy may be considerable. AO accuracy is especially reduced in patients showing large beat-to-beat BP variability or high HF.

Toxicokinetics of ibogaine and noribogaine in a patient with prolonged multiple cardiac arrhythmias after ingestion of internet purchased ibogaine.

BACKGROUND: Ibogaine is an agent that has been evaluated as an unapproved anti-addictive agent for the management of drug dependence. Sudden cardiac death has been described to occur secondary to its use. We describe the clinical effects and toxicokinetics of ibogaine and noribogaine in a single patient. For this purpose, we developed a LC-MS/MS-method to measure ibogaine and noribogaine plasma-concentrations. We used two compartments with first order absorption. CASE DETAILS: The maximum concentration of ibogaine was 1.45 mg/L. Our patient developed markedly prolonged QTc interval of 647ms maximum, several multiple cardiac arrhythmias (i.e., atrial tachycardia and ventricular tachycardia and Torsades des Pointes). QTc-prolongation remained present until 12 days after ingestion, several days after ibogaine plasma-levels were low, implicating clinically relevant noribogaine concentrations long after ibogaine had been cleared from the plasma. The ratio k12/k21 for noribogaine was 21.5 and 4.28 for ibogaine, implicating a lower distribution of noribogaine from the peripheral compartment into the central compartment compared to ibogaine. CONCLUSIONS: We demonstrated a linear relationship between the concentration of the metabolite and long duration of action, rather than with parent ibogaine. Therefore, after (prolonged) ibogaine ingestion, clinicians should beware of long-term effects due to its metabolite.

Bisoprolol in idiopathic pulmonary arterial hypertension: an explorative study.

While beta-blockers are considered contraindicated in pulmonary arterial hypertension (PAH), the prognostic significance of sympathetic nervous system over-activity suggests a potential benefit of beta-blocker therapy. The aim of this randomised, placebo-controlled, crossover, single centre study was to determine the effects of bisoprolol on right ventricular ejection fraction (RVEF) in idiopathic PAH (iPAH) patients. Additional efficacy and safety parameters were explored.Patients with optimally treated, stable iPAH (New York Heart Association functional class II/III) were randomised to placebo or bisoprolol. Imaging and functional measurements were performed at baseline, crossover and end of study.18 iPAH patients were included, because inclusion faltered before enrolment of the targeted 25 patients. 17 patients completed 6 months of bisoprolol, 15 tolerated bisoprolol, one patient required intravenous diuretics. Bisoprolol was associated with a lower heart rate (17 beats per minute, p=0.0001) but RVEF remained unchanged. A drop in cardiac index (0.5 L·min(-1)·m(-2), p=0.015) was observed, along with a trend towards a decreased 6-min walking distance (6MWD).Although careful up-titration of bisoprolol was tolerated by most patients and resulted in a decreased heart rate, no benefit of bisoprolol in iPAH was demonstrated. Decreases in cardiac index and 6MWD suggest a deteriorated cardiac function. The results do not favour the use of bisoprolol in iPAH patients.

Evaluating the optimal timing of revascularisation in patients with transient ST-segment elevation myocardial infarction: rationale and design of the TRANSIENT Trial.

Patients with chest pain and a prehospital ST-segment elevation myocardial infarction (STEMI) are preferably treated with immediate percutaneous coronary intervention (PCI). However, patients with normalization of symptoms and ST-segment elevation upon hospital arrival (transient STEMI) received inconsistent therapy due to logistic reasons and the absence of evidence or explicit guidelines. In this trial, the optimal timing of coronary angiography and subsequent revascularisation is investigated in patients presenting with transient STEMI. In this prospective, multicentre, randomized controlled clinical trial, 142 consecutive patients with initially acute chest pain and STEMI, whose symptoms and ST-segment elevation resolve upon admission, are randomized to immediate intervention or a delayed intervention. Primary outcome is infarct size measured at 4 days determined by cardiovascular magnetic resonance. Secondary outcomes are left ventricular function and volumes, myocardial salvage and microvascular injury at baseline; the change in left ventricular function, volumes and infarct size at 4 months; and major adverse cardiac events at 4 and 12 months. The TRANSIENT Trial evaluates whether a delayed invasive strategy (according to NSTEMI-guidelines) is superior to an immediate invasive strategy (according to STEMI-guidelines) in patients with a transient STEMI.

Renal denervation in heart failure with normal left ventricular ejection fraction. Rationale and design of the DIASTOLE (DenervatIon of the renAl Sympathetic nerves in hearT failure with nOrmal Lv Ejection fraction) trial.

Aim Increasing evidence suggests an important role for hyperactivation of the sympathetic nervous system (SNS) in the clinical phenomena of heart failure with normal LVEF (HFNEF) and hypertension. Moreover, the level of renal sympathetic activation is directly related to the severity of heart failure. Since percutaneous renal denervation (pRDN) has been shown to be effective in modulating elevated SNS activity in patients with hypertension, it can be hypothesized that pRDN has a positive effect on HFNEF. The DIASTOLE trial will investigate whether renal sympathetic denervation influences parameters of HFNEF. Methods DIASTOLE is a multicentre, randomized controlled trial. Sixty patients, diagnosed with HFNEF and treated for hypertension, will be randomly allocated in a 1:1 ratio to undergo renal denervation on top of medical treatment (n = 30) or to maintain medical treatment alone (n = 30). The primary objective is to investigate the efficacy of pRDN by means of pulsed wave Doppler echocardiographic parameters. Secondary objectives include safety of pRDN and a comparison of changes in the following parameters after pRDN: LV mass, LV volume, LVEF, and left atrial volume as determined by magnetic resonance imaging. Also, MIBG (metaiodobenzylguanidine) uptake and washout, BNP levels, blood pressure, heart rate variability, exercise capacity, and quality of life will be assessed. Perspective DIASTOLE is a randomized controlled trial evaluating renal denervation as a treatment option for HFNEF. The results of the current trial will provide important information regarding the treatment of HFNEF, and therefore may have major impact on future therapeutic strategies. Trail registration NCT01583881.

Assessment of intraventricular mechanical dyssynchrony and prediction of response to cardiac resynchronization therapy: comparison between tissue Doppler imaging and real-time three-dimensional echocardiography.

OBJECTIVE: We studied the comparability of left ventricular (LV) mechanical dyssynchrony assessment by tissue Doppler imaging (TDI) and real-time three-dimensional echocardiography (RT3DE) in patients with a wide range of LV ejection fractions and different causes of cardiomyopathy. In addition, we evaluated the ability of both techniques to predict response to cardiac resynchronization therapy (CRT). METHODS: A total of 90 patients and 30 healthy volunteers underwent both TDI and RT3DE. A subgroup of 27 patients underwent CRT and were evaluated before and 6 months after implantation. Mechanical dyssynchrony was measured with TDI using the standard deviation of time to peak systolic tissue velocity of 12 LV myocardial segments. With RT3DE, the standard deviation of time from QRS onset to minimal volume of 16 LV subvolumes was assessed. Indicators of response to CRT were a clinical improvement of >or= 1 New York Heart Association functional class, and reverse remodeling defined as a reduction of >or= 15% in LV end-systolic volume at 6 months. RESULTS: A moderate correlation (r = 0.581, P < .001) was observed between TDI and RT3DE. No significant difference in the presence of mechanical dyssynchrony by TDI and RT3DE was observed (53% vs 48%, respectively). Agreement between techniques was comparable between patients with ischemic and nonischemic cardiomyopathy. However, up to 30% nonagreement between the 2 techniques was found, depending on the severity of LV dysfunction. Of the 27 patients undergoing CRT, clinical response was observed in 70% of patients, whereas reverse remodeling occurred in 63% of patients. All baseline characteristics were similar between responders and nonresponders, except for mechanical dyssynchrony assessed by RT3DE, which was significantly higher in responders compared with nonresponders (10.1% +/- 2.6% vs 5.1% +/- 1.2% for clinical response, P < .001; 10.0% +/- 2.8% vs 6.3% +/- 2.3% for reverse remodeling, P = .001). By applying previously defined cutoff values, receiver operating characteristic curve analysis demonstrated a sensitivity of 58% with a specificity of 50% for TDI and a sensitivity of 95% with a specificity of 87% for RT3DE to predict clinical response to CRT. For prediction of reverse remodeling after CRT, sensitivity and specificity were 59% and 50% for TDI, and 88% and 60% for RT3DE, respectively. The optimal cutoff value for systolic dyssynchrony index by RT3DE of 6.7% yielded a sensitivity of 90% with a specificity of 87% to predict clinical response, and a sensitivity of 88% with a specificity of 70% to predict reverse remodeling. CONCLUSION: Marked differences between techniques are found for the presence of mechanical dyssynchrony when current cutoff values are applied, making interchangeability of these techniques uncertain. Assessment of mechanical dyssynchrony by RT3DE might be an appropriate alternative to TDI for accurate prediction of response to CRT.

Stroke work or systolic dP/dtmax to evaluate acute response to cardiac resynchronization therapy: are they interchangeable?

BACKGROUND: Cardiac resynchronization therapy (CRT) is characterized by a approximately 30% non-response. Invasive haemodynamic measurements are a traditional method to evaluate response to CRT. This study evaluates the correlation between acute changes in dP/dt(max) and Stroke Work (SW) during CRT. METHODS: Thirty-four CRT candidates were haemodynamically evaluated by pressure-volume loop analysis during biventricular pacing. RESULTS: Mean dP/dt(max) and SW at baseline were 854 +/- 198 and 5186 +/- 2349, and displayed an increase during pacing of 106 +/- 117 mmHg/s (13% +/- 14%) and 1303 +/- 3039 mL/mmHg (30% +/- 52%), respectively. No correlation was found between the percentage change in dP/dt(max) and SW (R = 0.06, P = ns). When defining response an augmentation of 10% relative to baseline for both parameters, 16 patients demonstrated an ambiguous response. CONCLUSION: Although both parameters display an average increase during pacing, the change relative to baseline values of SW and dP/dt(max) is not related.

Interventricular mechanical asynchrony in pulmonary arterial hypertension: left-to-right delay in peak shortening is related to right ventricular overload and left ventricular underfilling.

OBJECTIVES: The purpose of this study was to explore in pulmonary arterial hypertension (PAH) whether the cause of interventricular asynchrony lies in onset of shortening or duration of shortening. BACKGROUND: In PAH, leftward ventricular septal bowing (LVSB) is probably caused by a left-to-right (L-R) delay in myocardial shortening. METHODS: In 21 PAH patients (mean pulmonary arterial pressure 55 +/- 13 mm Hg and electrocardiogram-QRS width 100 +/- 16 ms), magnetic resonance imaging myocardial tagging (14 ms temporal resolution) was applied. For the left ventricular (LV) free wall, septum, and right ventricular (RV) free wall, the onset time (T(onset)) and peak time (T(peak)) of circumferential shortening were calculated. The RV wall tension was estimated by the Laplace law. RESULTS: The T(onset) was 51 +/- 23 ms, 65 +/- 4 ms, and 52 +/- 22 ms for LV, septum, and RV, respectively. The T(peak) was 293 +/- 58 ms, 267 +/- 22 ms, and 387 +/- 50 ms for LV, septum, and RV, respectively. Maximum LVSB was at 395 +/- 45 ms, coinciding with septal overstretch and RV T(peak). The L-R delay in T(onset) was -1 +/- 16 ms (p = 0.84), and the L-R delay in T(peak) was 94 +/- 41 ms (p < 0.001). The L-R delay in T(peak) was not related to the QRS width but was associated with RV wall tension (p < 0.05). The L-R delay in T(peak) correlated with leftward septal curvature (p < 0.05) and correlated negatively with LV end-diastolic volume (p < 0.05) and stroke volume (p < 0.05). CONCLUSIONS: In PAH, the L-R delay in myocardial peak shortening is caused by lengthening of the duration of RV shortening. This L-R delay is related to LVSB, decreased LV filling, and decreased stroke volume.

Effects of stimulation site on diastolic function in cardiac resynchronization therapy.

BACKGROUND: Cardiac resynchronization therapy (CRT) improves left ventricular (LV) systolic function and clinical status, and prolongs survival of patients suffering from heart failure. An optimal LV site selection is key with respect to improvements in systolic function, though whether a site-specific effect on diastolic function exists is unclear. This study compared the effects of CRT on changes in systolic and diastolic function from 2 LV stimulation sites. METHODS: We studied 21 patients in New York Heart Association functional classes >/= III, and a LV ejection fraction < 0.30 and QRS duration > 130 ms. CRT leads were placed in the right ventricle, right atrium, and coronary sinus tributaries. LV stimulation was applied from the postero-lateral and antero-lateral wall. A LV conductance catheter was used to measure LV systolic and diastolic function. Systolic responders had > 10% changes in dP/dt(max), and diastolic responders < 10% changes in tau during CRT versus baseline. Response was highly dependent on LV lead position for both diastolic and systolic function. Diastolic responders decreased from 29% to 10% of patients, and systolic responders from 76% to 48%, in the best versus the worst lead position, respectively. Improvements in diastolic function were less pronounced than in systolic function (relative change -14% vs +28%, P < 0.05). Overall, 45% were both systolic and diastolic responders, 17% were both systolic and diastolic nonresponders, and 38% had opposite responses. CONCLUSIONS: Changes in systolic and diastolic function were both highly dependent on the LV stimulation site. Diastolic function was less influenced by CRT and a high proportion of patients had discordant results.

Long-term follow-up of patients with refractory heart failure and myocardial ischemia treated with cardiac resynchronization therapy.

Studies in patients without coronary artery disease have shown the restoration of glucose metabolism by cardiac resynchronization therapy (CRT) without changes in myocardial perfusion. We report on the long-term outcome of CRT in 24 patients with severe heart failure (HF) and advanced coronary artery disease not amenable for revascularization. All patients had documented myocardial ischemia on stress (99)Tc-sestamibi single-photon emission computed tomography, and all underwent successful implantations of CRT systems. The mean left ventricular ejection fraction was 21%+/- 4%, 19 patients (79%) had anginal complaints and 20 (83%) had diffuse three-vessel disease. During a follow-up of 13 +/- 0.7 months, two patients died suddenly and one died of progressive HF. Among survivors, functional capacity decreased from New York Heart Association class 3.2 +/- 1.4 to 2.1 +/- 1.0 (P < 0.01), and the Minnesota questionnaire quality-of-life scores decreased from 43 +/- 15 to 28 +/- 13 (P < 0.01). Despite an increase from 264 +/- 104 to 385 +/- 121 m in distance walked in 6 minutes (P < 0.01), the number of anginal attacks/week remained unchanged (4.7 +/- 0.7 to 4.5 +/- 0.6). Patients with advanced HF, stable angina, and documented myocardial ischemia may undergo safe and successful implantations of CRT systems.